Alzheimer's disease is a progressive mental deterioration in a human resulting in loss of memory, confusion and disorientation, as well as, behavioral problems such as anxiety. Alzheimer's disease accounts for the majority of senile dementias and is a leading cause of death in adults. Currently-used treatments offer a small symptomatic benefit; however, no treatments to delay or halt the progression of the disease are as yet available.
The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain. Histologically, the brains of persons afflicted with Alzheimer's disease are characterized by a distortion of the intracellular neurofibrils and the presence of senile plaques composed of granular or filamentous argentophilic masses with an amyloid protein core, largely due to the accumulation of β-amyloid protein (Aβ) in the brain. Aβ accumulation plays a role in the pathogenesis and progression of the disease and is a proteolytic fragment of amyloid precursor protein (APP). APP is cleaved initially by β-secretase (BACE1, also referred to as memapsin 2) followed by γ-secretase to generate Aβ. Without being bound by theory, it is believed that one approach to the treatment of Alzheimer's disease is to inhibit the production of Aβ.
It has been discovered that the compounds described herein are potent inhibitors of BACE1. It has also been discovered that those compounds may offer therapeutic benefits to patients suffering from or in need of relief from Alzheimer's disease. The compounds described herein include a substituted polyamine backbone core structure. Without being bound by theory, it is believed herein that the backbone core structure is capable of additional positive binding interactions with BACE1. Those additional interactions may be responsible at least in part for the observed activity and the therapeutic potential of the compounds described herein, and the compositions containing them.
In one illustrative embodiment of the invention described herein, compounds of the following formula are described herein:
or a pharmaceutically acceptable salt thereof, wherein R, X1, X2, X3, A, Q1, R2, R3, R4, R5, R7, and q are defined below.
In another illustrative embodiment, compounds of the following formula are described herein:
or a pharmaceutically acceptable salt thereof, wherein R, X1, X2, X3, A, Q1, R2, R3, R4, R5, R6a, R6b, R7, and q are defined below.
In another illustrative embodiment, compounds of the following formula are described herein:
or a pharmaceutically acceptable salt thereof, wherein R, X1, X2, X3, A, Q1, R2, R3, R4, R5, R6a, R6b, R6c, R7, and q are defined below.
In addition, various genera and subgenera of each of R, X1, X2, X3, A, Q1, R2, R3, R4, R5, R6a, R6b, R6c, R7 and q are described herein. It is to be understood that all possible combinations of the various genera and subgenera of each of R, X1, X2, X3, A, Q1, R2, R3, R4, R5, R6a, R6b, R6c, R7, and q described herein represent additional illustrative embodiments of compounds of the invention described herein. It is to be further understood that each of those additional illustrative embodiments of compounds may be used in any of the compositions, methods, and/or uses described herein.
In another embodiment, compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with Alzheimer's disease. In another embodiment, methods for using the compounds and compositions for treating patients with Alzheimer's disease are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions containing them to a patient with Alzheimer's disease. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions for treating patients with Alzheimer's disease. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients with Alzheimer's disease are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with Alzheimer's disease.
It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds useful for treating Alzheimer's disease, including those compounds that may operate by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of Alzheimer's disease, such as compounds administered to improve cognitive function, that act as anxiolytics and/or antipsychotics to control behavior, and the like.